The present invention relates to a process for the preparation of ethers deriving from hydroxybenzoic acids. These products are particularly useful as intermediates for pharmaceutical syntheses, in agrarian chemistry, in dyes, fragrances, pharmaceutical solutions for dental cements and as adhesive components.
More specifically, the present invention relates to a process for the production of o-ethoxybenzoic acid (2-EBA) used in particular as an intermediate for pharmaceutical syntheses.
Preparation methods of ethers of hydroxybenzoic acids are known in literature. For example, in Zh. Org. Khim., vol. 23, Nr. 3, pages 667-668, the preparation is described of alkyl ethers of hydroxybenzoic acid starting from an aqueous solution of potassium hydroxide, containing o-hydroxybenzoic acid, and from an alkyl halide. The reaction, catalyzed by crown-ethers, also produces high quantities of ether with the esterified carboxylic function. This ether-ester must be treated in a second phase to saponify the esterified function by means of hydrolysis.
With the aim of overcoming this drawback, a synthesis method alternative to the previous one was proposed in the patent U.S. Pat. No. 5,344,968, which comprises the reaction between a chlorobenzoic acid and a C1-C5 alkyl alcohol in the presence of a catalytic system consisting of a copper salt and an alkyl amine. Although characterized by a better selectivity, with respect to the method described above, the process of patent U.S. Pat. No. 5,344,968 still requires the use of a complex catalytic system which, at the end of the reaction, must be separated from the end-product.
U.S. Pat. No. 4,161,611 teaches the preparation of a methyl ether of 2-hydroxy3,6-dichlorobenzoic acid with methyl chloride in water and sodium hydroxide, the pH being maintained during the reaction in the range of 10-12 by the periodic addition of NaOH.
The Applicant has now found that it is possible to obtain alkyl ethers of hydroxybenzoic acids in a single passage by reacting salicylic acid with an alkyl chloride, in the presence of a base, without the formation of an ether-ester. More specifically, operating according to the process object of the present invention, it is possible to obtain alkoxybenzoic acid directly with good yields and a high selectivity by reacting, in water, an alkaline salt of salicylic acid with an alkyl chloride and an alkaline base fed simultaneously but so as to maintain a slight excess of alkaline base in reaction, according to the following reaction scheme: 
Operating according to this process, the following advantages are obtained with respect to the known art:
use of an economic reagent, such as alkyl chloride, which makes the process competitive also from an industrial point of view;
use of an economic and simple solvent such as water operating in a single aqueous phase;
possibility of also carrying out the reaction in a mixed water/non-miscible solvent (for example toluene) system, thus obtaining a reduction in the reaction pressure;
elimination of reaction by-products such as alkyl esters of etherified salicylic acid, and the consequent elimination of subsequent hydrolysis steps of said ether-esters to obtain the corresponding ethers only.
An object of the present invention therefore relates to a process for the preparation of ethers of hydroxybenzoic acid having general formula (I): 
wherein R1 represents a linear or branched C1-C6 alkyl group or an alkylaromatic group wherein the alkyl group contains from 1 to 4 carbon atoms and wherein R1 represents a hydrogen atom or a C1-C4 alkoxy, phenoxy, benzyloxy group, or a C1-C4 alkyl radical, a C2-C4 alkenyl radical, a xe2x80x94COCH3 or Yxe2x80x94CHO acetyl radical, wherein Y represents a simple bond or a C1-C4 alkyl radical, or it represents an xe2x80x94NO2 or xe2x80x94NR3R4 group wherein R3R4, the same or different, are selected from a hydrogen atom or a C1-C4 alkyl radical, which comprises reacting a hydroxybenzoic acid, optionally substituted, with an XR1 halide, wherein X is a halogen such as chlorine, in a basic environment and in an aqueous or aqueous/organic biphasic solvent.
According to the present invention, the preferred but non-limiting compound is that having general formula (I), wherein R1 is an ethyl radical in ortho position with respect to the carboxylic group and wherein R2 represents a hydrogen atom.
The synthesis reaction, which can be carried out by feeding the reagents either in continuous or batchwise, but preferably in continuous, takes place between the hydroxybenzoic acid optionally substituted, preferably salicylic acid, and an alkyl halide, preferably ethyl chloride, in the presence of a base in order to fix the halogen which is released during the reaction in aqueous solvent. The feeding of the reagents is generally carried out in continuous feeding the base in advance with respect to the ethyl chloride.
Preferred bases are aqueous sodium or potassium hydroxides. Organic bases such as trialkylamines can also be used, which block the hydrochloric acid in the hydrochloride form of the amine. Sodium hydroxide used with molar ratios alkyl halide/NaOH ranging from 1/1 to 1/3, preferably equal to 1/5, is particularly preferred. The reaction is carried out in an autoclave at a pressure ranging from 1 to 15 atm and at a temperature ranging from 80xc2x0 C. to 160xc2x0 C., preferably from 110xc2x0 C. to 130xc2x0 C.
To favour the conversion of the hydroxybenzoic acid, it is preferable to use an excess of alkyl halide with respect to the aromatic substrate. The molar ratios hydroxybenzoic acid/alkyl halide range from 1/1.5 to 1/4, preferably from 1/2 to 1/2.5.
When the reaction solvent is water alone, this is used in such a quantity as to have a weight ratio hydroxybenzoic acid/water, at the end of the feeding, ranging from 1/2 to 1/6, preferably from 1/3 to 1/4. When the water is mixed with a non-miscible organic solvent, for example toluene or xylenes, the latter is present in a quantity ranging from 5 to 50% by volume with respect to the total water+solvent volume.